Metabolic syndrome, including type 2 diabetes and associated complications such as obesity and dyslipidemia, are of major impact on social and economic significance. Although anti-diabetic treatments improve insulin resistance, they offer little protection from eminent cardiovascular risk associated with type 2 diabetes. Therefore, there is the need for developing new treatments that have insulin-sensitizing and cholesterol/triglycerides-lowering effects.
Diabetes mellitus is a polygenic disorder affecting a significant portion of the people in the world. It is divided into two types. In type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone that regulates glucose utilization. In type 2 diabetes, or noninsulin dependent diabetes mellitus (NIDDM), patients often have plasma insulin levels that are at the same compared to nondiabetic humans; however, these patients have developed a resistance to the insulin stimulating effect on glucose and lipid metabolism in the main insulin-sensitive tissues, i.e., muscle, liver and adipose tissues, and the plasma insulin levels are insufficient to overcome the pronounced insulin resistance. Type 2 diabetes consists of over 90% of all diabetes. It is a metabolic disorder characterized by hyperglycemia leading to secondary complications such as neuropathy, nephropathy, retinopathy, hypertriglyceridemia, obesity, and other cardiovascular diseases generally referred as metabolic syndrome.
The treatment generally prescribed for type 2 diabetes has been a combination of diet, exercise, and oral hypoglycemic agents, commonly sulfonylurea and biguanides. However, sulfonylurea therapy has many problems associated with primary and secondary failure of efficacy, incidence of hypoglycemia, and obesity. The biguanides therapy can induce lactic acidosis, nausea and diarrhea. Hence, a drug that can control plasma glucose tightly without significant side effects would be an important addition to diabetes therapy. Recently, a class of compounds termed thiazolidinediones has been shown to reduce hyperglycemia by sensitizing insulin action without additional insulin secretion, and without causing undesirable hypoglycemia, even at elevated doses. Their effect is proposed to be a result of initiation and modulation of adipocyte differentiation by agonist activity of PPARgamma. This class of compounds that is able to activate PPARgamma has been demonstrated clinically effective in treatment of type 2 diabetes (AVANDIA from GSK and ACTOS from Lilly/Takeda). Although the exact link from activation of PPARgamma to change in glucose metabolism, most notably a decrease in insulin resistance in muscle, has not yet been clarified, the link is via free fatty acids in such that activation of PPARgamma induces lipoprotein lipase, fatty acid transport protein and acyl-CoA synthetase in adipose tissue but not in muscle cells. This effect, in turn, reduces the concentration of free fatty acids in plasma dramatically, leading to eventual switch from fatty acid oxidation to glucose oxidation in high metabolic state of tissues, such as skeletal muscle and other tissues, due to substrate competition and pathway compensation. That results in a decreased insulin resistance in those tissues. Further, activation of PPARgamma modulates a subset of genes in controlling glucose and energy homeostasis, which leads to decrease blood glucose level (T. M. Wilson et al. “The PPARs: from orphan receptors to drug discovery” J. Med. Chem. 2000 43:527–50; A. Chawla et al. “Nuclear receptors and lipid physiology: Opening the X-files”. Science 2001 294:1866–70)
Despite the advances made with the thiazolidinedione class of antidiabetes agents, serious unacceptable side effects including cardiac hypertrophy, hemodilution and liver toxicity have limited their clinical use. In the United States and Japan, several cases of liver damage and drug-related deaths due to liver damage have been reported. Further, PPARgamma-selective ligands induce adipocyte differentiation and white fat accumulation that leads to obesity, an important factor linking directly to the onset or the consequence of type 2 diabetes. Such unwanted effects will eventually compromise the insulin-sensitizing benefit of PPARgamma ligands. Hence, there is a definite need for a safe and efficacious agent for the treatment of type 2 diabetic patients that possesses dual activities of insulin-sensitizing as well as lowering white adipose deposition by regulating free fatty acids and triglycerides contents.
PPARgamma is a member of ligand-activated nuclear hormone receptor superfamily and expressed primarily in adipose tissues. A class of ligands named fibrates that are known to have triglyceride- and cholesterol-lowering activity activates another member of this family, the PPARalpha, which is mainly expressed in tissues such as liver. PPARalpha stimulates peroxisomal proliferation that enhances fatty acid oxidation, leading to reduced fatty acids level in blood (Keller and Wahli: Trends Endocrin Metab 1993, 4:291–296). Most recently, PPARdelta was reported to modulate lipid metabolism in which PPARdelta serves as a widespread regulator of fat burning. In vitro, activation of PPARdelta in adipocytes and skeletal muscle cells promotes fatty acid oxidation and utilization. Targeted activation of PPARdelta in adipose tissue in animals where PPARalpha is much less expressed, specifically induces expression of genes required for fatty acid oxidation and energy dissipation, which in turn leads to improved lipid profiles and reduced adiposity. Importantly, these animals are completely resistant to both high-fat diet-induced and genetically predisposed (Lepr(db/db)) obesity. Acute treatment of Lepr(db/db) mice with a PPARdelta agonist depletes lipid accumulation. In parallel, PPARdelta-deficient mice challenged with high-fat diet show reduced energy uncoupling and are prone to obesity (Wang Y X et al., Cell 2003 Apr. 18;113(2):159–70). The transcriptional repression of atherogenic inflammation by ligand-activated PPARdelta was also reported, which further indicates the importance of PPARdelta in combating cardiovascular diseases (Lee, C H et al., Science 302:453–457, 2003).
The PPARs form heterodimers with Retinoid X Receptor (RXR). The RXR/PPAR heterodimers thus play an important role in controlling cellular events such as glucose and lipid homeostasis, and adipocyte differentiation. Several classes of new chemical compounds were reported to have PPARalpha and gamma dual activities that are beneficial in the treatment and/or prevention of metabolic syndromes in animal and in human (US 2002/0065268 A1, U.S. Pat. No. 6,369,055 B1, WO01/55085A1, WO97/25042, WO02/26729 A2, a WO00/08002). However, dual agonists of the compounds having PPARalpha and delta or PPARalpha and gamma, or PPARdelta and gamma activities could offer a new opportunity for additional benefits against type 2 diabetes as well as cardiovascular complications with improved safety profiles.